Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](F)=[N:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([C:25]1[CH:30]=[CH:29][C:28]([N:14]2[CH2:15][CH2:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])([CH3:17])[CH2:12][CH2:13]2)=[N:27][CH:26]=1)=[O:32])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)nc1
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.31 g, 1.28 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 6-fluoro-nicotinic acid tert-butyl ester (0.21 g, 1.07 mmol). The reaction mixture was stirred at 80° C. for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 30% ethyl acetate in hexane to provide 4-benzyloxycarbonylamino-4methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylic acid tert-butyl ester. MS (CI) m/z 426 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.74(d, 1H), 7.97 (dd, 1H), 7.35 (m, 5H), 7.26 (s, 1H), 5.07 (s, 2H), 4.68 (s, 1H), 3.97 (m, 2H), 3.37 (m, 2H), 2.08 (m, 2H), 1.66 (m, 2H), 1.56 (s, 9H), 1.42 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(3 g, 13.4 mmol) in THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (13.5 ml, 13.5 mmol, Aldrich). The resulting orange solution was stirred at ambient temperature under nitrogen for 30 min. To the reaction was added a solution of 1-(bromomethyl)-4-chloro-2-(trifluoromethyl)benzene (3.7 g, 13.5 mmol, Fluorochem) in THF (5 ml). The resulting orange solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (125 ml) and aqueous sodium bicarbonate (75 ml). The phases were separated and the organic phase washed with aqueous sodium bicarbonate (50 ml). The combined aqueous phases were washed with ethyl acetate (75 ml). The organic phases were combined, dried, filtered and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 100 g×2 using a 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (2.83 g); LCMS: (System 4) MH+=416, tRET=3.14 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-nitropyridin-2-amine (0.5 g, 3.59 mmol) was slurried in DCM (12 ml). TEA (2.5 ml, 18 mmol) and DMAP (88 mg, 0.72 mmol) were added. 2,2-dimethylpropanoyl chloride was added prop wise and the mixture stirred at RT overnight. The mixture was diluted into water (30 ml):saturated sodium bicarbonate (aq, 10 ml), extracted with DCM (3×30 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The material was purified by chromatography on SiO2 eluting with 10% acetone: hexanes to give the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[Na].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O>O>[N:16]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[C:5]([CH3:14])[C:6]([Cl:13])=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2ccc(Cl)c(C)c2nc1Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ccc(Cl)c(C)c2nc1-n1cncn1
Temperature: 100 °C
Reaction time: 25 h
Yield: 96 %

Procedure:
A mixture of 2.26 g of 2,7-dichloro-3,8-dimethyl-quinoline, 1.1 g of the sodium salt of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 25 hours. The reaction mixture is poured into 100 ml of water and the precipitated product is filtered. Thus 2.48 g of the desired compound are obtained, yield 96%. Mp.: 147°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:15][C@H:10]2[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31]>CO>[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:15])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1S
Reactant: CNC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Solvent: CO
Solvent: Cc1ccccc1C
Product: CNC(=O)[C@H](O)[C@@H](Sc1ccccc1N)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-methylpropionamide (829 mg) and xylene (10 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (551 mg) and anhydrous ferric chloride (0.065 mg) in methanol (0.08 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with xylene, and dried at 60° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-methylpropionamide (1.06 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13]1([CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.B(F)(F)F.CCOCC>O1CCOCC1>[CH:22]1([CH2:20][CH:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: OC(CC1CCCCC1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1oc2ccccc2c(O)c1C(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a time-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 1.01 g of 2-cyclohexyl-1-phenylethanol of Preparation 19 in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=l with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 30% to 60% ethyl acetate in hexanes to yield 110 mg of the title product as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N[C:21](N)=[O:22].O>CN1C(=O)CCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:21](=[O:22])[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1N
Reactant: NC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c(=O)c2cc(Oc3ccc(F)cc3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Compound (1D) (23 g, 0.09 mol) and urea (25.42 g, 0.41 mol) in NMP (150 mL) were heated to 170° C. for 18 h. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and stirred for 1 h. The precipitate was filtered, washed with water, and dried to afford 22.7 g of 6-(2,4-difluoro-phenoxy)-1H-quinazoline-2,4-dione (1E).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:54][C@@H:55]2[CH2:59][NH:58][C@H:57]([C:60]([NH:62][C@:63]3([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:65][C@H:64]3[CH:66]=[CH2:67])=[O:61])[CH2:56]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:54][C@@H:55]2[CH2:59][N:58]([C:34](=[O:36])[C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C@H:57]([C:60]([NH:62][C@:63]3([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:65][C@H:64]3[CH:66]=[CH2:67])=[O:61])[CH2:56]2)(=[O:52])=[O:53])=[CH:47][CH:46]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c2ccc(Br)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
HATU (27.3 g) was added to the solution of (2S)-2-[(tert-butoxycarbonyl)amino]non-8-enoic acid (19.5 g) in DMF (100 ml) and the solution was stirred 15 minutes. The reaction mixture was cooled to 0° C. Then, the amine from Step 3 (31.8 g) in DMF (200 ml) (cooled to 0° C.) was added followed by DIPEA (11.40 ml). The solution was stirred at 0° C. for 1 hour. Hydrochloric acid (1M) was added and the mixture was extracted with diethyl ether (3×). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (40.2 g) as a white foam. LRMS (ES+) m/z 762.2 (M+Na)+.
Reaction SMILES: [N:1]([CH2:4][C:5]([F:27])([F:26])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-]>CO.C(Cl)Cl.[Pd]>[NH2:1][CH2:4][C:5]([F:27])([F:26])[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN=[N+]=[N-])c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN)c2c1
Reaction time: 3.5 h
Yield: 83.2 %

Procedure:
To a solution of diethyl 1-(3-azido-2,2-difluoropropyl)-1H-indole-2,6-dicarboxylate (2.5 g, 7.8 mmol) in methanol:CH2Cl2 (1:1, 60 mL) is added 10% palladium on carbon (1.4 g, 1.3 mmol). The reaction mixture is stirred for 3.5 h under H2 atmosphere. The reaction mixture is filtered and the filtrate is concentrated to afford the title crude compound (2.3 g) which is used in the next step without purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16].C(Cl)Cl.[C-:20]#[N:21].[K+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[C:20]([CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]1=[O:16])#[N:21]
Reactant: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Reactant: [C-]#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCC1CC(=O)N(c2ccc(F)cc2)C1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
A mixture was prepared of 48.3 g (0.2 moles) 3-chloromethyl-1-(4-fluorophenyl)-pyrrolidine-2,5-dione (according to Example 1), 300 ml methylene chloride and 7 g hexadecyltrimethylammonium chloride, dissolved in 80 ml water. To this mixture, a solution of 28.6 g (0.43 moles) potassium cyanide in 90 ml water was added dropwise at 0° C., and then stirred for 4 hours at 0° C. and another 12 hours at 20° C. The resulting phases were then separated with the organic phase being washed with water and dried with sodium sulfate. Finally, methylene chloride was distilled off and the residue dissolved in 250 ml toluene. Upon standing, the desired product crystallized. The actual yield was 44.1% of the theoretical yield. Melting point 97° C.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])=[O:4].O>ClCCl>[NH2:1][S:3]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])=[O:4]
Reactant: CCOc1ccc(C(=O)OC)c(S(=O)(=O)Cl)c1
Reactant: N
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Liquified ammonia (4.4 mL, 180 mmol) was added to a stirred solution of methyl 2-(chlorosulfonyl)-4-ethoxybenzoate (22.1 g, 79.3 mmol) in dichloromethane (221 mL) at -70° C. The reaction mixture was allowed to warm to -10° C. and was held at this temperature for 30 minutes. The mixture was then poured into water (221 mL). More water and dichloromethane were used for rinsing, and tetrahydrofuran (ca. 40 mL) was also added. The layers were shaken and separated, and the aqueous layer was extracted with dichloromethane (2×221 mL). The combined dichloromethane solutions were washed with water (221 mL), and the aqueous wash was back-extracted with dichloromethane (ca. 120 mL). The combined dichloromethane solutions were dried (Na2SO4), and filtered. Rotary evaporation of the solvent left crude product as an off-white crystalline solid (18.1 g). This was dissolved in hot methanol (ca. 200 mL) and hot filtered. The solution was boiled down to a volume corresponding to 3 mL/g methanol. After seeding and cooling with the aid of an ice bath, the crystals were collected, rinsed with ice-cold methanol and hexanes, and dried. Methyl 2-(aminosulfonyl)-4-ethoxybenzoate (15.3 g) was obtained as white crystalline needles melting at 146°-148° C. PMR (CDCl3, 200 mHz): δ7.91 (d, 1H, H ortho to CO2CH3); 7.68 (d, 1H, H ortho to SO2NH2); 7.04 (dd, 1H, H para to SO2NH2); 5.91 (broad s, 2H, NH2); 4.14 (q, 2H, OCH2CH3); 3.95 (s, 3H, CO2CH3); 1.45 (t, 3H, OCH2CH3). IR (Nujol): 3348 (m, NH); 3241 (m, NH); 1692 (s, C=O) cm-1.
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)C.[2H]C(Cl)(Cl)Cl.[2H][C:26]([2H])([2H])[O:27][2H]>>[CH3:26][O:27][CH:5]1[CH2:4][CH2:3][CH2:8][CH2:7]/[C:6]/1=[CH:9]\[C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=2[N:14]=1
Reactant: [2H]OC([2H])([2H])[2H]
Reactant: CCC1CCC(=Cc2nc3cc(O)ccc3o2)CC1
Agent: [2H]C(Cl)(Cl)Cl
Product: COC1CCCC/C1=C\c1nc2cc(O)ccc2o1

Procedure:
2-(4-Ethylcyclohexylidenemethyl)benzoxazol-5-ol (13C-NMR [CDCl3/CD3OD)]: 165.203, 160.259, 155.998, 145.294, 142.867, 114.835, 111.739, 109.631, 105.497, 40.269, 38.948, 35.672, 34.921, 31.423, 30.305, 12.672);
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH:52]1[CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:54]6[CH2:55][CH2:56][N:51]([CH3:50])[CH:52]([CH3:57])[CH2:53]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC1CNCCN1C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C)C(C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (150 mg, 0.226 mmol), 1,2-dimethylpiperazine (45.7 mg, 0.40 mmol), sodium triacetoxyborohydride (95 mg, 0.45 mmol) and AcOH (18 μl, 0.314 mmol) in 1,2-dichloroethane (DCE) (6 mL) was stirred overnight at room temperature. LC/MS showed that the reaction was complete. The reaction was diluted with EtOAc; the organic layer washed with dilute aq. NaOH, then sat. aq. NaCl and dried [Na2SO4], then concentrated to a viscous taffy. The material was purified on a Gilson HPLC using reverse phase (acetonitrile-water with 0.1% TFA). Fractions containing the desired product were combined, the MeOH removed, the aqueous layer treated with EtOAc and 1N NaOH. The mixture was vigorously extracted with EtOAc (2×), the extract was washed with a small amount of sat. aq. NaCl; dried [Na2SO4], then concentrated to a glassy, creamy tan, coloured foam (0.1002 g). LC-MS m/z 761.5 (M+H)+, 0.76 min (ret time).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[O:30][N:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:32]=[C:31]([CH2:33][OH:34])[O:30][N:29]=4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(CO)on3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-(5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M43) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (113 mg).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]=1[I:13])C>ClC1C=CC=CC=1Cl.CO>[C:14]1([C:10]2[N:9]3[C:3](=[O:2])[NH:4][N:5]=[CH:6][C:8]3=[C:12]([I:13])[N:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)NN=C(C)c1nc(-c2ccccc2)[nH]c1I
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]ncc2c(I)nc(-c3ccccc3)n12
Reaction time: 0.33 h
Yield: 70.4 %

Procedure:
3-[1-(5-Iodo-2-phenyl-4-imidazolyl)ethylidene]-carbazic acid methyl ester (1.01 gm., 0.0027 mole) is dissolved in a mixture of o-dichlorobenzene (150 ml.) and methanol (15 ml.). The solution is heated to the boiling point and boiled for 20 minutes allowing solvent to distill off partially. The reaction mixture is chromatographed over a silica gel column and eluted with a hexane-ethyl acetate (2:1) mixture to yield the title product (0.63 gm., 0.0019 mole). Recrystallization from ethyl acetate-hexane yields the product as yellow needles, m.p. 176°-189° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]2[C:8](=[O:19])[N:9]([CH2:16][CH2:17][CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5][N:4]=1.[H-].[Na+].[C:22](Cl)(=[O:25])[O:23][CH3:24]>CN(C=O)C>[CH3:24][O:23][C:22]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:16][CH2:17][CH3:18])[C:8](=[O:19])[C:7]=2[C:3]([NH:2][CH3:1])=[N:4]1)=[O:25]
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2c2ccccc21
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)nn(C(=O)OC)c2c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
In 70 ml of DMF was suspended 1.69 g (6.6 mmol) of Compound 1, and 0.33 g (8.3 mmol) of 60% sodium hydride was added and dissolved therein. To the mixture was added 0.80 ml (10 mmol) of methyl chlorocarbonate, followed by stirring at room temperature for 1 hour. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, passed through a silica gel column, and eluted with chloroform. The main fraction collected was dried under reduced pressure and recrystallized from water-containing ethanol to obtain 1.03 g (50%) of the titled compound as a colorless crystal.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](O)[CH2:14][CH3:15]>>[CH2:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH2:14][CH3:15]
Reactant: CCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CCCON1C(=O)c2ccccc2C1=O

Procedure:
The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and 1-propanol. m/e (DCI) 223 (MH+NH3+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH2:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH:16][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1nc2c(OCc3cccc(Cl)c3)cccn2n1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5cccc(Cl)c5)cccn4n3)cc2)CC1

Procedure:
260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.